14-22478914-C-T

Variant names:

• chr14-22478914-C-T
• rs1872159
• ENST00000390482.1:c.41C>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000390482.1(TRAJ57):​c.41C>T​(p.Thr14Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 762,968 control chromosomes in the GnomAD database, including 9,944 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1401 hom., cov: 26)
  • Exomes 𝑓: 0.14 (8543 hom.)
• Consequence: TRAJ57 ENST00000390482.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63

Genes affected

TRAJ57 (HGNC:12089): (T cell receptor alpha joining 57) T cell receptors recognize foreign antigens which have been processed as small peptides and bound to major histocompatibility complex (MHC) molecules at the surface of antigen presenting cells (APC). Each T cell receptor is a dimer consisting of one alpha and one beta chain or one delta and one gamma chain. In a single cell, the T cell receptor loci are rearranged and expressed in the order delta, gamma, beta, and alpha. If both delta and gamma rearrangements produce functional chains, the cell expresses delta and gamma. If not, the cell proceeds to rearrange the beta and alpha loci. This region represents the germline organization of the T cell receptor alpha and delta loci. Both the alpha and delta loci include V (variable), J (joining), and C (constant) segments and the delta locus also includes diversity (D) segments. The delta locus is situated within the alpha locus, between the alpha V and J segments. During T cell development, the delta chain is synthesized by a recombination event at the DNA level joining a D segment with a J segment; a V segment is then joined to the D-J gene. The alpha chain is synthesized by recombination joining a single V segment with a J segment. For both chains, the C segment is later joined by splicing at the RNA level. Recombination of many different V segments with several J segments provides a wide range of antigen recognition. Additional diversity is attained by junctional diversity, resulting from the random additional of nucleotides by terminal deoxynucleotidyltransferase. Five variable segments can be used in either alpha or delta chains and are described by TRAV/DV symbols. Several V and J segments of the alpha locus are known to be incapable of encoding a protein and are considered pseudogenes. [provided by RefSeq, Aug 2016]

TRA (HGNC:12027):

TRD-AS1 (HGNC:56197): (TRD antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAJ57	unassigned_transcript_2250	c.41C>T	p.Thr14Met	missense_variant	Exon 1 of 1
TRA		n.22478914C>T		intragenic_variant
TRD-AS1	NR_148361.1	n.225+2327G>A		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAJ57	ENST00000390482.1	c.41C>T	p.Thr14Met	missense_variant	Exon 1 of 1	6		ENSP00000452248.1
TRD-AS1	ENST00000514473.2	n.225+2327G>A		intron_variant	Intron 2 of 2	2
TRD-AS1	ENST00000556777.2	n.562+2327G>A		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16209 AN: 150770 Hom.: 1399 Cov.: 26

Gnomad AFR AF: 0.0466

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0728

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.0920

GnomAD3 exomes AF: 0.143 AC: 33266 AN: 232838 Hom.: 3828 AF XY: 0.147 AC XY: 18671 AN XY: 127286

Gnomad AFR exome AF: 0.0474

Gnomad AMR exome AF: 0.0657

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.491

Gnomad SAS exome AF: 0.209

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.140 AC: 85660 AN: 612080 Hom.: 8543 Cov.: 0 AF XY: 0.143 AC XY: 47733 AN XY: 334480

Gnomad4 AFR exome AF: 0.0495

Gnomad4 AMR exome AF: 0.0666

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.445

Gnomad4 SAS exome AF: 0.206

Gnomad4 FIN exome AF: 0.174

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.107 AC: 16200 AN: 150888 Hom.: 1401 Cov.: 26 AF XY: 0.113 AC XY: 8292 AN XY: 73656

Gnomad4 AFR AF: 0.0466

Gnomad4 AMR AF: 0.0727

Gnomad4 ASJ AF: 0.100

Gnomad4 EAS AF: 0.478

Gnomad4 SAS AF: 0.223

Gnomad4 FIN AF: 0.170

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.0920

Alfa AF: 0.102 Hom.: 910

Bravo AF: 0.0956

Asia WGS AF: 0.311 AC: 1084 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1872159; hg19: chr14-22947903; COSMIC: COSV66606336;